Abstract
The recent Ebola virus outbreak has highlighted the therapeutic potential of antisera and renewed interest in this treatment approach. While human convalescent sera may not be readily available in the early stages of an outbreak, antisera of animal origin can be produced in a short time frame. Here, we compared adjuvanted virus-like particles (VLP) with recombinant modified vaccinia virus Ankara and vesicular stomatitis virus (VSV), both expressing the Ebola virus antigens. The neutralizing antibody titers of rabbits immunized with adjuvanted VLPs were similar to those immunized with the replication-competent VSV, indicating that presentation of the antigen in its native conformation rather than de novo antigen expression is essential for production of functional antibodies. This approach also yielded high-titer antisera against Nipah virus glycoproteins, illustrating that it is transferable to other virus families. Multiple-step immunoglobulin G purification using a two-step 20–40% ammonium sulfate precipitation followed by protein A affinity chromatography resulted in 90% recovery of functionality and sustained in vivo stability. Adjuvanted VLP-based immunization strategies are thus a promising approach for the rapid generation of therapeutic antisera against emerging infections.
Highlights
Outbreaks of emerging viruses occur with worrying regularity, and while some are quickly controlled locally, others become public health events of global concern
To assess their ability for induction of high functional antibody titers, we produced Ebola virus (EBOV) virus-like particles (VLP) by cotransfecting human embyonic kidney-293 (HEK-293) cells with plasmids encoding for the EBOV Zaire strain Mayinga matrix protein (VP40) and the full-length membrane-anchored glycoprotein (GP).[31]
First antibodies against EBOV-GP were detected after 2 weeks, with approximately 10-fold higher titers in the Sigma and TiterMax adjuvant groups
Summary
Outbreaks of emerging viruses occur with worrying regularity, and while some are quickly controlled locally, others become public health events of global concern. Whole blood from convalescent donors was given as a postexposure treatment during the 1995 Kikwit outbreak with seven of eight patients surviving the infection.[14] post-exposure treatment of nonhuman primates with whole blood from convalescent donors did not replicate the successes seen in human patients.[15] More recently, 84 patients treated with convalescent plasma failed to show significant improvement in survival during the 2014 West African outbreak,[16] but definitive interpretation of these data is difficult because the antibody titers and virus-neutralizing activity of the convalescent plasma was not reported. Post-exposure passive transfer of sera from hamsters immunized with either vaccinia or vesicular stomatitis viruses (VSVs) expressing the NiV-G protein provides protection from lethal virus challenge in a hamster model,[19,20] as do murine monoclonal antibodies that bind either NiV-F or NiV-G,21 and a human monoclonal antibody with neutralizing activity against the related Hendra virus G protein in ferrets.[22]
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